With very few exceptions such as sodium chloride, drugs are susceptible to aging loads such as water, oxygen and light and glass ampules have been in use for their storage since many years ago. However, with the recent advances in pharmaceutical science, material engineering, production methodology, production equipment, etc., these pharmaceutical containers are being replaced by glass vials and plastic (such as polyolefins, e.g. polyethylene, polypropylene, etc., ethylene-vinyl acetate copolymer, polyethylene terephthalate, polyvinyl chloride, etc.) containers which are easy for those engaged in medical practice to handle and easy to dispose of after use and the utilization of such plastic containers, in particular, is rapidly spreading of late.
However, unlike glass, plastics are inherently permeable to gas and moisture and have the disadvantage that containers made thereof cannot be used for all kinds of drugs. Recently, materials which are almost as impervious to gas and moisture as glass, such as a laminate film carrying a vapor-deposited aluminum layer or an aluminum foil, a laminate film carrying a vapor-deposited silicon monoxide layer, a multi-layer film consisting of plural materials such as polyethylene terephthalate, polyvinyl alcohol, polyvinylidene chloride, ethylene-vinyl alcohol copolymer, etc. have been developed and today plastics with an oxygen permeability rate of not more than 1.0 cc/m.sup.2 .multidot.24 hrs/1 atm. and a moisture permeability rate of not more than 1.0 g/m.sup.2 .multidot.24 hrs/1 atm. are available on the market and finding ever broadening usage and application.
Meanwhile, drugs are generally stable in the bulk form but if they are dissolved and administered to patients, the low pH values of the solutions would not only damage the local tissue at the administration site but also induce systemic disturbances or result in poor absorption. Therefore, a variety of pharmaceutical contrivances has so far been made to avoid the troubles. By way of illustration, assuming that the pharmaceutical composition contains a strongly acidic powdery substance such as the hydrochloride or an acidic powdery drug whose neutral salt would be unstable, it is common practice to formulate the drug with a bicarbonate to insure the proper pH on dissolution or convert it to the neutral salt which is more readily absorbed at the time of administration.
Moreover, drugs which are unstable in solution, for example certain antibiotics, are supplied in the powdery form but since these drugs in general are sparingly soluble in aqueous vehicles, a bicarbonate as a source of carbon dioxide gas, which assists in dissolution, is added as a solubilizer.
On the other hand, sodium hydrogen carbonate is contained as an alkalizing agent in dialysis fluid compositions for artificial kidney use and for the purpose of insuring the ease of handling and reducing the cost of shipment, the recent tread is toward converting such liquid compositions to powdery or granular preparations (e.g. Japanese Patent Application Kokai H3-38527 and Kokai H3-74331).
The bicarbonate contained in such pharmaceutical compositions liberates water and carbon dioxide gas with time but it is well known that in a closed system there is established an equilibrium among the bicarbonate, carbonate, water and carbon dioxide as indicated by the following relation (1). EQU 2HCO.sub.3.sup.- .revreaction.CO.sub.3.sup.2- +H.sub.2 O+CO.sub.2( 1)
However, when a bicarbonate-containing powdery pharmaceutical composition is supplied in a plastic (such as polyolefins, e.g. polyethylene, polypropylene, etc., ethylene-vinyl acetate copolymer, polyvinyl chloride, etc.) container, the carbon dioxide gas and water liberated from the bicarbonate find their way out through the plastic container which is permeable to gas and moisture. As a result, the balance of the above relation (1) is tipped to the right to yield the carbonate so that when the composition is dissolved for administration, the intrinsic objects of adding the bicarbonate, namely supply of HCO.sub.3.sup.-, neutralization of the drug, and assistance in dissolution, cannot be accomplished. Moreover, the solution after reconstitution undergoes increase of pH to affect the stability of the drug solution. For the protection of a powdery pharmaceutical composition containing a drug liable to decompose on absorption of moisture and a bicarbonate, as supplied in a plastic container, from the decomposition due to moisture, it might be contemplated to dispose a desiccant externally of the plastic container and wrapping the plastic container and desiccant together in a wrapping material with proven performance qualities, e.g. an oxygen permeability rate of not more than 1.0 cc/m.sup.2 .multidot.24 hrs/ 1 atm. and a water permeability rate of not more than 1.0 g/m.sup.2 .multidot.24 hrs/1 atm., such as a laminate film carrying a vapor-deposited silicon oxide layer, a composite laminate film comprising a plurality of materials such as polyethylene terephthalate, polyvinyl alcohol, polyvinylidene chloride, ethylene-vinyl alcohol copolymer, etc. or a laminate film having a vapor-deposited aluminum layer or an aluminum foil which is equivalent to glass in barrier performance. In such cases, there still occur events similar to those encountered when a bicarbonate-containing powdery composition is simply filled into a plastic container. Thus, the water and carbon dioxide gas liberated from the bicarbonate are adsorbed on the included desiccant so that the balance of said relation (1) is tipped to the right to cause the formation of carbonate and, hence, an elevation of pH of the solution after reconstitution.
The present invention provides a new technology which overcomes all the above-mentioned problems associated with the provision of a bicarbonate-containing powdery pharmaceutical preparation in a plastic container which is permeable to moisture and gas by insuring an increased carbon dioxide concentration in the container, allowing the moisture to be dissipated to the extent not affecting the quality of the drug, and inhibiting decomposition of the bicarbonate and formation of the carbonate to suppress the increase of pH after reconstitution and allow the inherent objects of incorporation of the carbonate, namely supply of HCO.sub.3.sup.-, neutralization of the drug and assistance in dissolution, to be accomplished without compromise.